Adenine phosphoribosyltransferase deficiency

Summary

Adenine phosphoribosyltransferase deficiency (MONDO:0013869) is a disease caused by APRT (GenCC Definitive), with 2 cohort genes and 6 clinical trials. Top therapeutic interventions include allopurinol and febuxostat.

At a glance

• Prevalence: 1-9 / 100 000 (Specific population) [Orphanet-validated]
• Causal gene: APRT (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 124
• Phenotypes (HPO): 18
• Clinical trials: 6

Clinical features

Epidemiology

Prevalence records

4 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000	1.5	Specific population	Validated
Point prevalence	1-9 / 100 000	3.7	Japan	Validated
Point prevalence	1-9 / 100 000	6.7	Iceland	Validated
Point prevalence	1-9 / 100 000		Europe	Not yet validated

Signs & symptoms

Clinical features (HPO)

18 HPO clinical features (Orphanet curated; top 18 by frequency):

HPO ID	Term	Frequency
HP:0012379	Abnormal enzyme/coenzyme activity	Very frequent (80-99%)
HP:0000083	Renal insufficiency	Frequent (30-79%)
HP:0000093	Proteinuria	Frequent (30-79%)
HP:0000787	Nephrolithiasis	Frequent (30-79%)
HP:0000822	Hypertension	Frequent (30-79%)
HP:0001919	Acute kidney injury	Frequent (30-79%)
HP:0012622	Chronic kidney disease	Frequent (30-79%)
HP:0100518	Dysuria	Frequent (30-79%)
HP:0000010	Recurrent urinary tract infections	Occasional (5-29%)
HP:0000016	Urinary retention	Occasional (5-29%)
HP:0000019	Urinary hesitancy	Occasional (5-29%)
HP:0000791	Uric acid nephrolithiasis	Occasional (5-29%)
HP:0003774	Stage 5 chronic kidney disease	Occasional (5-29%)
HP:0005110	Atrial fibrillation	Occasional (5-29%)
HP:0011848	Abdominal colic	Occasional (5-29%)
HP:0012587	Macroscopic hematuria	Occasional (5-29%)
HP:0030157	Flank pain	Occasional (5-29%)
HP:0100520	Oliguria	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	adenine phosphoribosyltransferase deficiency
Mondo ID	MONDO:0013869
MeSH	C538228
OMIM	614723
Orphanet	976
DOID	DOID:0060350
ICD-11	753682703
NCIT	C121564
SNOMED CT	124274002
UMLS	C0268120
MedGen	82772
GARD	0000546
Is cancer (heuristic)	no

Also known as: 2,8-dihydroxyadenine urolithiasis · 2,8-dihydroxyadeninuria disease · adenine phosphoribosyltransferase deficiency · APRT deficiency · APRTD · Dihydroxyadeninuria

Data availability: 124 ClinVar variants · 4 GenCC gene-disease records · 30 cell lines.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inborn disorder of amino acid and other organic acid metabolism › inborn disorder of amino acid metabolism › adenine phosphoribosyltransferase deficiency

Related subtypes (32): disorder of methionine catabolism, inborn serine deficiency, cerebral creatine deficiency syndrome, inborn organic aciduria, gamma-amino butyric acid metabolism disorder, homocystinuria, urea cycle disorder, adenylosuccinate lyase deficiency, systemic primary carnitine deficiency disease, cystathioninuria, hyperlysinemia, Brunner syndrome, glycine encephalopathy, aminoacylase 1 deficiency, hyperphenylalaninemia due to tetrahydrobiopterin deficiency, inborn disorder of tryptophan metabolism, inborn disorder of proline metabolism, inborn disorder of ornithine metabolism, inborn disorder of amino acid transport, inborn disorder of histidine metabolism, inborn disorder of phenylalanine and tyrosine metabolism, inborn disorder of branched-chain amino acid metabolism, arakawa syndrome 2, 2-methylacetoacetyl CoA thiolase deficiency, albinism, hyperphenylalaninemia due to DNAJC12 deficiency, inborn disorder of the metabolism of sulfur-containing amino acids and hydrogen sulfide, inborn disorder of glycine and serine metabolism, inborn disorder of ornithine, proline and hydroxyproline metabolism, inborn disorder of glutamate/glutamine and aspartate/asparagine metabolism, hyperglycinemia, transient neonatal, tetrahydrobiopterin (BH4)-deficient hyperphenylalaninemia

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

124 retrieved; paginated sample, class counts are floors:

44 pathogenic, 41 uncertain significance, 20 likely pathogenic, 9 conflicting classifications of pathogenicity, 4 likely benign, 3 benign/likely benign, 3 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
18294	NM_000485.3(APRT):c.518TCT[1] (p.Phe174del)	APRT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
18295	NM_000485.3(APRT):c.321+2dup	APRT	Pathogenic	no assertion criteria provided
18296	NM_000485.3(APRT):c.407T>C (p.Met136Thr)	APRT	Pathogenic	criteria provided, single submitter
18297	NM_000485.3(APRT):c.194A>T (p.Asp65Val)	APRT	Pathogenic	criteria provided, multiple submitters, no conflicts
18298	NM_000485.3(APRT):c.294G>A (p.Trp98Ter)	APRT	Pathogenic	criteria provided, multiple submitters, no conflicts
18299	NM_000485.3(APRT):c.258_261dup (p.Lys88fs)	APRT	Pathogenic	no assertion criteria provided
18300	NM_000485.3(APRT):c.329T>C (p.Leu110Pro)	APRT	Pathogenic	no assertion criteria provided
18302	NM_000485.3(APRT):c.542G>C (p.Ter181Ser)	APRT	Pathogenic	no assertion criteria provided
3359185	NM_000485.3(APRT):c.482C>A (p.Ser161Ter)	APRT	Pathogenic	no assertion criteria provided
4074265	NM_000485.3(APRT):c.3G>C (p.Met1Ile)	APRT	Pathogenic	criteria provided, single submitter
41012	NM_000485.3(APRT):c.448G>T (p.Val150Phe)	APRT	Pathogenic	no assertion criteria provided
988021	NM_000485.3(APRT):c.522_524del (p.Ser175del)	APRT	Pathogenic	criteria provided, single submitter
988022	NM_000485.3(APRT):c.526C>T (p.Leu176Phe)	APRT	Pathogenic	no assertion criteria provided
988023	NM_000485.3(APRT):c.526_530del (p.Leu176fs)	APRT	Pathogenic	no assertion criteria provided
988024	NM_000485.3(APRT):c.532C>T (p.Gln178Ter)	APRT	Pathogenic	no assertion criteria provided
988026	NM_000485.3(APRT):c.543A>T (p.Ter181Cys)	APRT	Pathogenic	no assertion criteria provided
988027	NM_000485.2:c.-1_*1del	APRT	Pathogenic	no assertion criteria provided
988028	NM_000485.3(APRT):c.1A>G (p.Met1Val)	APRT	Pathogenic	criteria provided, multiple submitters, no conflicts
988029	NM_000485.3(APRT):c.2T>C (p.Met1Thr)	APRT	Pathogenic	criteria provided, single submitter
988030	NM_000485.3(APRT):c.3G>A (p.Met1Ile)	APRT	Pathogenic	no assertion criteria provided
988031	NM_000485.3(APRT):c.23dup (p.Val9fs)	APRT	Pathogenic	criteria provided, single submitter
988033	NM_000485.3(APRT):c.81-3C>G	APRT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
988035	NM_000485.3(APRT):c.82G>C (p.Asp28His)	APRT	Pathogenic	no assertion criteria provided
988037	NM_000485.3(APRT):c.98T>C (p.Leu33Pro)	APRT	Pathogenic	no assertion criteria provided
988038	NM_000485.3(APRT):c.119G>C (p.Arg40Pro)	APRT	Pathogenic	no assertion criteria provided
988040	NM_000485.3(APRT):c.180_181insT (p.Ile61fs)	APRT	Pathogenic	no assertion criteria provided
988041	NM_000485.3(APRT):c.184_187+22del	APRT	Pathogenic	no assertion criteria provided
988042	NM_000485.3(APRT):c.188-3C>G	APRT	Pathogenic	no assertion criteria provided
988043	NM_000485.3(APRT):c.188-145_296del	APRT	Pathogenic	no assertion criteria provided
988045	NM_000485.3(APRT):c.199C>T (p.Arg67Ter)	APRT	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 2 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
APRT	Definitive	Autosomal recessive	adenine phosphoribosyltransferase deficiency	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
APRT	Orphanet:976	Adenine phosphoribosyltransferase deficiency
CDT1	Orphanet:2554	Ear-patella-short stature syndrome

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
APRT	HGNC:626	ENSG00000198931	P07741	Adenine phosphoribosyltransferase	gencc,clinvar
CDT1	HGNC:24576	ENSG00000167513	Q9H211	DNA replication factor Cdt1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
APRT	Adenine phosphoribosyltransferase	Catalyzes a salvage reaction resulting in the formation of AMP, that is energically less costly than de novo synthesis.
CDT1	DNA replication factor Cdt1	Required for both DNA replication and mitosis.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
APRT	Other/Unknown	no		PRTase_dom, Ade_phspho_trans, PRTase-like
CDT1	Other/Unknown	no		CDT1_Gemini-bd-like, Cdt1_C, WH_DNA-bd_sf

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
lower esophagus mucosa	1
skin of abdomen	1
skin of leg	1
mucosa of paranasal sinus	1
oocyte	1
superficial temporal artery	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
APRT	287	ubiquitous	marker	skin of abdomen, skin of leg, lower esophagus mucosa
CDT1	185	ubiquitous	marker	mucosa of paranasal sinus, superficial temporal artery, oocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
APRT	3,481
CDT1	2,813

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
APRT	P07741	16
CDT1	Q9H211	6

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 25. Enrichment computed across 2 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective APRT disrupts adenine salvage	1	5710.0×	0.003	APRT
Nucleotide salvage defects	1	2855.0×	0.003	APRT
Diseases of nucleotide metabolism	1	2855.0×	0.003	APRT
Nucleotide salvage	1	571.0×	0.011	APRT
Purine salvage	1	439.2×	0.011	APRT
G1/S-Specific Transcription	1	178.4×	0.015	CDT1
Activation of the pre-replicative complex	1	163.1×	0.015	CDT1
DNA Replication Pre-Initiation	1	158.6×	0.015	CDT1
Metabolism of nucleotides	1	150.3×	0.015	APRT
Switching of origins to a post-replicative state	1	150.3×	0.015	CDT1
Synthesis of DNA	1	150.3×	0.015	CDT1
DNA Replication	1	119.0×	0.016	CDT1
G1/S Transition	1	116.5×	0.016	CDT1
Mitotic G1 phase and G1/S transition	1	92.1×	0.017	CDT1
S Phase	1	90.6×	0.017	CDT1
Orc1 removal from chromatin	1	89.2×	0.017	CDT1
Assembly of the pre-replicative complex	1	69.6×	0.021	CDT1
Diseases of metabolism	1	40.2×	0.034	APRT
Cell Cycle, Mitotic	1	24.1×	0.054	CDT1
Cell Cycle	1	18.0×	0.068	CDT1
Innate Immune System	1	12.8×	0.092	APRT
Neutrophil degranulation	1	11.5×	0.096	APRT
Disease	1	6.5×	0.155	APRT
Immune System	1	6.5×	0.155	APRT
Metabolism	1	5.8×	0.165	APRT

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
adenine salvage	1	8426.0×	8e-04	APRT
DNA replication preinitiation complex assembly	1	8426.0×	8e-04	CDT1
mitotic pre-replicative complex assembly	1	8426.0×	8e-04	CDT1
response to sorbitol	1	4213.0×	0.001	CDT1
negative regulation of DNA-templated DNA replication	1	2808.7×	0.001	CDT1
IMP salvage	1	1685.2×	0.001	APRT
regulation of nuclear cell cycle DNA replication	1	1685.2×	0.001	CDT1
GMP salvage	1	1404.3×	0.001	APRT
AMP salvage	1	1404.3×	0.001	APRT
mitotic DNA replication initiation	1	1404.3×	0.001	CDT1
purine ribonucleoside salvage	1	1203.7×	0.001	APRT
DNA replication checkpoint signaling	1	648.1×	0.002	CDT1
grooming behavior	1	561.7×	0.002	APRT
regulation of DNA-templated DNA replication initiation	1	526.6×	0.002	CDT1
attachment of mitotic spindle microtubules to kinetochore	1	526.6×	0.002	CDT1
positive regulation of DNA replication	1	290.6×	0.004	CDT1
negative regulation of cell cycle	1	145.3×	0.008	CDT1
mitotic cell cycle	1	66.9×	0.016	CDT1
cell division	1	23.1×	0.043	CDT1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 1

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
APRT	1	3
CDT1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CRENOLANIB	3	APRT

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
APRT	2	Binding:2

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

1 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
CRENOLANIB	3	APRT

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	1	APRT
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	CDT1

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
CDT1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 6.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	5
PHASE4	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT02752633	PHASE4	COMPLETED	Effect of Allopurinol and Febuxostat on Urinary 2,8-Dihydroxyadenine Excretion
NCT00588562	Not specified	RECRUITING	Rare Kidney Stone Consortium Patient Registry
NCT02026388	Not specified	RECRUITING	Rare Kidney Stone Consortium Biobank
NCT02780297	Not specified	RECRUITING	Prospective Research Rare Kidney Stones (ProRKS)
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns
NCT06065852	Not specified	RECRUITING	National Registry of Rare Kidney Diseases

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
ALLOPURINOL	4	1
FEBUXOSTAT	4	1